Safety, Efficacy and Pharmacokinetics of NNC-0156-0000-0009 in Previously Treated Children With Haemophilia B.

Inhibitors were analysed with either the Nijmegen modified factor IX Bethesda assay or a heat/cold Nijmegen modified factor IX Bethesda assay. Number of participants who developed inhibitory antibodies against factor IX are reported.

Inhibitors were analysed with either the Nijmegen modified factor IX Bethesda assay or a heat/cold Nijmegen modified factor IX Bethesda assay. Number of participants who developed inhibitory antibodies against factor IX are reported.

The number of bleeding episodes per participant during routine prophylaxis was assessed using the individual annualised bleeding rates (bleeding episodes per participant per year).

Description of the haemostatic effect of nonacog beta pegol when used for treatment of bleeding episodes was measured and listed according to the four point scale for haemostatic response as below:

• Excellent - abrupt pain relief and/or clear improvement in objective signs of bleeding within 8 hours after a single infusion.
• Good - noticeable pain relief and/or improvement in signs of bleeding within 8 hours after a single injection.
• Moderate - probable or slight beneficial effect within the first 8 hours after the first injection but requiring more than one infusion within 8 hours.
• Poor - no improvement, or worsening of symptoms within 8 hours after two injections.

A success rate was calculated based on counting good or excellent as successes and poor and moderate as failures.

The incremental recovery was calculated by dividing the baseline-subtracted factor IX activity Units per milliliter (U/mL) measured in plasma 30 min after dosing by the dose injected at time 0 expressed as units per kilogram (U/kg) body weight.

The mean pre-dose factor IX levels was measured with the one-stage clotting assay during the trial. Geometric mean of the lowest activity of factor IX recorded at week 0 (immediately before next dose was given).

Terminal half life is presented at week 0, 30 minutes until one week after first exposure.

The mean pre-dose factor IX levels was measured with the one-stage clotting assay during the trial. The estimated mean of the lowest activity recorded immediately before next dose was given from week 4 to EOT approximately (week 544). Data is reported for specific age groups in which participants were a part of at any time from week 4 to EOT, not at specific time points assessed from week 4 to EOT. The analysis is based on a mixed model on the log-transformed plasma concentrations with participant as a random effect and the mean trough level is presented back-transformed to the natural scale. Considering the time frame, actual age groups (adolescents and adults) are added for this outcome measure.

An adverse event (AE) was any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Here, data is presented for all adverse events (serious adverse events and other adverse events) from week 0 to EOT approximately (week 544). Data is reported for specific Age Groups in which participants were a part of at any time from week 0 to EOT, not at specific time points assessed from week 0 to EOT (approximately week 544). Considering the time frame, actual age groups (adolescents and adults) are added for this outcome measure.

A SAE was an experience that at any dose resulted in any of the following: death, a life-threatening experience a), In-patient hospitalisation or prolongation of existing hospitalisation b) a persistent or significant disability/incapacity c) a congenital anomaly/birth defect, Important medical events d) that did not result in death, were life-threatening a) or required hospitalization. Here, data is presented from week 0 to EOT (approximately week 544). Data is reported for specific Age Groups in which participants were a part of at any time from week 0 to EOT, not at specific time points assessed from week 0 to EOT (approximately week 544). Considering the time frame, actual age groups (adolescents and adults) are added for this outcome measure.

The following events were defined as MESIs: -Medication errors concerning trial products, -Administration of wrong drug,

• Wrong route of administration,
• Administration of a high dose with the intention to cause harm, e.g. suicide attempt,
• Administration of an accidental overdose: more than 20 % from the intended dose,
• Inhibitor formation against factor IX (FIX),
• Thromboembolic events,
• Anaphylactic reaction.
• Allergic reaction including, but not limited to, any acute immunoglobulin E (IgE) mediated reaction or delayed type hypersensitivity.

Here, data is presented from week 0 to EOT (approximately week 544). Data is reported for specific Age Groups in which participants were a part of at any time from week 0 to EOT, not at specific time points assessed from week 0 to EOT (approximately week 544). Considering the time frame, actual age groups (adolescents and adults) are added for this outcome measure.

Participants were examined for the development of antibodies against HCP. Number of participants who developed antibodies against HCP is presented.

Consumption of nonacog beta pegol for treatment of bleeding episodes International units per kilogram per year (IU/Kg/year) per participant is presented from week 0 to EOT approximately (week 544). Data is reported for specific Age Groups in which participants were a part of at any time from week 0 to EOT, not at specific time points assessed from week 0 to EOT (approximately week 544). Considering the time frame, actual age groups (adolescents and adults) are added for this outcome measure.

Average dose of nonacog beta pegol for treatment of bleed from start to stop of bleed is presented from week 0 to EOT approximately (week 544) in international units per kilogram per bleed (IU/Kg/bleed). Data is reported for specific Age Groups in which participants were a part of at any time from week 0 to EOT, not at specific time points assessed from week 0 to EOT (approximately week 544). Considering the time frame, actual age groups (adolescents and adults) are added for this outcome measure.

Number of doses of FIX consumed for the treatment of bleeding episodes is presented from week 0 to EOT approximately (week 544). Here, data of number of doses of FIX for the treatment of bleeding episodes is reported among all the participants in an arm. Data is reported for specific Age Groups in which participants were a part of at any time from week 0 to EOT, not at specific time points assessed from week 0 to EOT (approximately week 544). Considering the time frame, actual age groups (adolescents and adults) are added for this outcome measure.

Area under the curve activity versus time profile from time zero to 168 hours post dose of nonacog beta pegol is presented.

Clearance of nonacog beta pegol after single dose is presented.

Mean residence time (MRT) of nonacog beta pegol after single dose is presented.

Volume of distribution at steady state (Vss) of nonacog beta pegol is presented.

FIX activity (international units per milliliter (IU/mL)) at 30 minutes after single dose is presented.

Mean FIX activity at 30 minutes post-dosing from week 4 to EOT approximately (week 544) (C30min) (steady state) is presented.

The Dutch institute of Prevention and Health and the Leiden University Hospital (TNO-AZL) preschool quality of life clustered into 12 multi-item scales is used to assess the health-related quality of life, such as children's motor, communication, emotions, and body structure. Suitable for children from 6 months to 6 years old (TAPQOL). Parents fill in according to the child's condition. Higher score (range 0-100) represents better outcome. The scale range for each of 12 multi-item scales was (0-100) with high score representing better outcome. In this study, the TAPQOL was assessed for children of age 0-3 years.

Number of participants with health economic impact of N9-GP treatment through characterisation of general hospitalisation is presented. Number of participants hospitalised for 0 & 1 day is presented.

Health economic impact of N9-GP treatment is presented through number of intensive care hospitalization days.

Health economic impact of N9-GP treatment through number of days bleedings caused missing school or studies. Number of participants who missed school or studies for 0,1 and 2 days are presented.

Health economic impact of N9-GP treatment through number of days the patient used mobility aids (wheelchair and/or crutches) is presented.

Health economic impact of N9-GP treatment through number of days bleeding caused parents to miss work is presented from week 0 to EOT approximately (week 544).

Haemophilia quality of life clustered into 11 multi-item scale which is used to assess haemophilia related quality of life such as children's physical health, feeling, family, friends, sport, treatment, dealing with haemophilia, view of a patient. Here, HAEMO-QOL was assessed for the children of age group 8-12 years. The scale range for each of 11 multi-item scale was 0-100 with high scores indicating low quality of life. Multi-item scores and total score were calculated using the following formula: 1/4(Sum of answered items / number of answered items - 1) x 100. HAEMO-QOL scores range from a 0 to 100 scale where high scores (nearing 100) indicate a low quality of life rating.

Haemophilia treatment satisfaction change from baseline (screening week -6) to week 176 (visit 17) is presented. The treatment satisfaction of a bleed with N8-GP was assessed using HEMO-SAT assessment tool which contains a questionnaire with 6 domains (Ease and convenience, efficacy, burden, specialist/nurses, centre/hospital, general satisfaction). The scale range for each 6 domains was (0-100) with lower score indicating higher treatment satisfaction. HEMO-SAT was assessed for the children of age group 4-7 years and 8-12 years. Domain score and total score were calculated using following formula - 1/4 (sum of answered items / Number of answered item - 1) x 100. HEMO-SAT scores range from 0-100, where low scores reflecting greater treatment satisfaction.